Fatty acids synthesis occurs at very high rates in tumor tissues, as first demonstrated more than half a century ago. Importantly, 14C glucose incorporation studies have shown that in tumor cells almost all fatty acids derive from de novo synthesis despite adequate nutritional supply. Prostate adenocarcinomas (PCa) overexpressing FAS display aggressive biologic behavior, suggesting that FAS overexpression confers a selective growth advantage. We have demonstrated that deregulated FAS expression in immortalized human prostate epithelial cells and as a transgene directed to the murine prostate results in invasive adenocarcinoma and prostatic intraepithelial neoplasia, respectively. The metabolic syndrome (MS), characterized by insulin resistance, central obesity and hypertension, is associated with inactivation of the master energy-sensor kinase AMPK and has recently been related to higher PCa incidence in large epidemiological studies. AMPK, when activated, inhibits FAS activity abolishing its oncogenic properties. Our preliminary data demonstrate that low serum levels of adiponectin, an endogenous activator of AMPK, significantly predict poor PCa survival. Taken together, these results strongly suggest a biological link between the metabolic syndrome, AMPK, FAS and PCa. The overarching hypothesis of this proposal is that FAS overexpression is the effector tumorigenic pathway of sustained AMPK inhibition. To validate this hypothesis, we will utilize a multidisciplinary approach that combines cell biology, animal model studies, tissue-based approaches and germline polymorphism correlations with PCa progression in large, annotated cohorts of PCa patients. Specifically, we will a) determine whether AMP kinase is a molecular target for inhibiting FAS activity;b) assess selected potential mechanisms of FAS mediated oncogenicity in PCa such as activation of pathways by palmitoylation of key regulatory genes c) assess whether genetic variations in the loci encoding AMPK, FAS, and their regulatory genes are predictors of prostate cancer progression and survival using haplotype tagging single nucleotide polymorphisms (SNPs);and d) relate the functional status of the FAS/AMPK axis to the metabolic syndrome in tissues from the same cohorts. The experiments proposed will establish FAS as a metabolic oncogene in prostate cancer, will solidify the link between the metabolic syndrome, obesity and prostate cancer through the master energy regulator kinase AMPK and establish FAS, and its regulators/effectors, as therapeutic targets in PCa. PUBLIC HEALTH RELEVANCE: In this proposal we are studying the role of key metabolic enzymes in prostate cancer. We are specifically focusing on a metabolic enzyme which is central to the control of obesity and blood glucose control in humans. The data resulting from this proposal, which includes epidemiologic, mouse model and human tumor analyses, will provide the long sought molecular link between diet, obesity and prostate cancer. In addition, this research that will likely results in novel therapeutic approaches in this disease.